2.1 Chirality in Pharmacology
The concept of chirality is basic to organic and biochemistry and has become a significant factor in determining the actions of a pharmacologic agent. An atom, particularly a carbon atom, is said to be chiral or stereogenic when it is bound to four different atoms or groups in a tetrahedral arrangement. All four atoms or groups must be different in order to make the central atom a chiral center. The importance of this is that such an arrangement can not be superimposed on its mirror image by any rotation of bonds or positioning of the molecule. The two molecules are isomers, that is they have the same empirical formula, but they are not identical and short of breaking and remaking bonds they can not be made identical.
Molecules that differ in the spatial arrangement of their atoms but have the same points of attachments are called stereoisomers. Enantiomers are a subgroup of stereoisomers that are nonsuperimposable mirror images. All molecules that contain stereogenic or chiral centers must have enantiomers. If a molecule can be superimposed on its mirror image by rotation or any motion other than bond making and breaking then they are identical and not enantiomers. A molecule that has more than one chiral center may generate multiple stereoisomers and these are called diastereomers.
Enantiomers are named according to a convention which assigns absolute descriptors R or S to the two possible arrangements of groups around a chiral center. Cahn R. S., Ingold C. R., Prelog V. Angew. Chem. (Int Ed.), 5, 385-415 (1966). Enantiomers have similar or identical physiochemical properties. However, they differ in their ability to rotate the plane of plane-polarized light while in solution. Enantiomers will rotate the plane of the light in equal amounts but in opposite directions and are therefore referred to as optical isomers. The ability to rotate the plane of polarized light is often used in the designation of the enantiomer. If the isomer rotates the plane of plane polarized light to the right it is dextrorotatory indicated by a (+) before the name of the compound. The isomer that rotates light to the left is termed levorotatory, indicated by a (-) prefix. The ability of an isomer to rotate the plane of light gives information about the physical property of the material but it does not give information concerning the 3-dimensional spatial arrangement or absolute configuration of the molecule as indicated by prefixes R and S. This complete name of an isomer includes (+) or (-) to indicate its optical properties and an R or S to indicate the molecules absolute configuration.
The variation of absolute configuration embodied in stereoisomers and enantiomers is of profound importance in nature. This is shown by the normal predominance of one enantiomer over another in naturally occurring molecules, e.g., L-amino acid, D-glucose, L-peptides, D-ribonucleotides. In contrast, synthetically made chemicals when made from achiral precursors generally are racemates or roughly equal mixtures of both enantiomers.
This has historically been true of the majority of drugs used to treat human disease which, for the most part, have been manufactured and used therapeutically in their racemic form. It has been calculated that 25% of all drugs on the markets today are chiral molecules and that approximately 80% of these are used as racemates. Lehmann, F. P. A. (1986), Trends Pharmacol. Sci., 7, 281-285.
For some therapeutic agents, chirality may not be important. However, until recently little was known about the effect of enantiomeric differences or stereoselectivity on the pharmacokinetics or pharmacodynamics of drugs. Over the past 10-15 years, there has been increased interest in pharmaceutical stereochemistry. It is now known that enantiomers of a given drug may have markedly different properties in a biological system. These different actions may be due to pharmacokinetic differences, such as effect on protein binding, storage, transport, metabolism, or clearance. Enantiomers may also show differential pharmacodynamic activity and show stereoselectivity in the manner in which they bind to and activate receptors. This selectivity should be expected in drug receptor interactions since many of the natural ligands are themselves chiral, e.g., neurotransmitters, hormones, endogenous peptides, etc. In addition, stereoisomers present as components of racemic mixtures may interact with each other in complex and poorly understood ways.
The recent increase in interest in and attention to pharmaceutical stereochemistry has occurred both because of an increased understanding of the unique properties of enantiomers and because there have been many developments in assymetric synthesis and chiral separation technology. New synthesis techniques have been developed which use chiral starting material or chiral reagents or catalysts which promote enantioselective synthesis. Large scale chromatographic recrystalization techniques and enzymatic reactions have now allowed pharmaceutical companies to produce single enantiomers on a large scale in a cost effective manner.
The effect of chirality on drug action is complex and may involve any or all systems in the body which are capable of reacting to a chiral molecule in an asymmetric or enantioselective manner.
Any active process can be expected to show enantiomeric selectivity or specificity. An active process may involve receptor interaction, enzyme action or binding specificity. In practice, the processes which may involve enantioselectivity include absorption, distribution including protein and tissue binding, storage and transport, metabolism, biliary and renal clearance and receptor binding and activation. Any one of these active processes alone or in combination may affect the therapeutic actions of a stereoisomer in vivo.